1. Subject of the Invention
The present invention refers to a process for the preparation of calcium phosphate cements and their application as bio-materials, which obvious objective is to allow their use in bone surgery and odontology.
2. Field of the Invention
This invention corresponds to the field of the industrial manufacture of bio-materials for bone surgery and odontology.
3. Description of Prior Art
Calcium and orthophosphate ions are regularly contained in body fluids and in the mineral substance forming parts of bones, dentine and dental enamel.
These are calcium orthophosphates, which additionally contain sodium, magnesium and carbonates. Sintered hydroxyapatite and calcium tri-phosphate, as well as other synthetic calcium orthophosphates, implanted in a number of test animals, as well as human beings, have been shown to be bio-compatible.
It has been observed from the use of these kinds of materials that they are bone growth promoters, that is, after implantation in bone tissue they promote their own growth.
A negative aspect of calcium sintered orthophosphates for use in surgery is that they have to be molded prior to the intervention, while orthophosphate cements do not show this disadvantage, because of their cement nature which allows them to be molded by the surgeon during the intervention.
At present the existence of solids corresponding to the system Ca(OH).sub.2 --H.sub.3 PO.sub.4 --H.sub.2 O at room or physiologic temperature is already known. Cement formulations are also known for the calcium orthophosphate system. Finally, other formulations are known from other inventions, for which reason they are excluded from the patent disclosure.
Concerning the solids belonging to the Ca(OH).sub.2 --H.sub.3 PO.sub.4 --H.sub.2 O system, a table is included in the following in which the solids which may be formed in this system at ambient or body temperature are described.
Given the fact that pH in bone in the vicinity of osteoclasts, osteoblasts and other osteocites may vary in a range between approximately 5 and 8, it has been observed that the final result of the solidification or setting reaction in a calcium orthophosphate cement will generally adopt the CDA form, which in physiological conditions will incorporate sodium and carbonate ions.
In bloodstream the apatites Ca.sub.8.5 Na.sub.1.5 (PO.sub.4).sub.4.5 (CO.sub.3).sub.2.5 or NCCA and Ca.sub.9 (PO.sub.4).sub.4.5 (CO.sub.3).sub.1.5 (OH).sub.1.5 or HCDHA may be formed by precipitation.
Given the fact that magnesium ions may be present, the final result may consist in magnesium whitlockite or MWH.
PHA could also result by the action of some fluorides.
In each of the above cases, the intermediate formation of DCPD or OCP is also possible.
In case that in a formulation of calcium orthophosphate some solidification reaction appears, it will be due to the framework constituted with the recently formed crystals.
As consequence, the best results which can be expected from a calcium orthophosphate cement, as concerns mechanical properties, consist in that this cement may come close to the mechanical characteristics of hard dental gypsum or other hard gypsum formations in which the framework of similar crystals (dicalcium sulphate dihydrate) is the mechanism for solidification or setting.
The solids appearing in the system Ca(OH).sub.2 --H.sub.3 PO.sub.4 --H.sub.2 O at ambient temperature or physiological temperature (1) are those shown in following table 1:
TABLE 1 __________________________________________________________________________ Abbreviation Ca/P Formula Formation conditions and relative __________________________________________________________________________ stability MCPM 0.5 Ca(H.sub.2 PO.sub.4).sub.2 H.sub.2 O Established below pH 2 approximately. Brushite 1.0 CaHPO.sub.4.2H.sub.2 O Established at pH between 2 and 4, rapid or DCPD nucleation and growth up to pH &gt; 6.5. OCP 1.33 Ca.sub.8 (HPO.sub.4).sub.2 (PO.sub.4).sub.4.5H.sub.2 O Rapid nucleation and growth in pH 6.5 to 8, more stable than DCPD or ACP in the same range. ACP 1.5 Ca.sub.3 (PO.sub.4).sub.2.H.sub.2 O This substance appears as a first stage when the precipitation takes place at high concentrations with pH between 4 and 8, however it spontaneously transforms into DCPD, OCP or CDA. By any means, by the incorporation of magnesium ions it will transform into magnesium whitlockite NWH is as stable as CDA. CDA 1.5 Ca.sub.9 (HPO.sub.4)(PO.sub.4).sub.5 OH This calcium poor apatite does not spontaneously precipitate, however it has DCPD or OCP as precursors. By any means, it may rest indefinitely in metastable balance with aqueous solution. PHA 1.67 Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 The precipitated hydroxyapatite is the most stable calcium orthophosphate. It only precipitates above pH 8. By any means, its nucleation with low pH maybe started by fluoride ions. -- .infin. Ca(OH).sub.2 This solid is stable only with a high pH in absence of orthophosphates. __________________________________________________________________________
Concerning cement formulations for the calcium orthophosphate system, any water based or water solution based cement as intermediate fluid medium, contains the following components:
a) An acidic component which may emit H.sup.+ ions which may be converted into a solid salt by reaction with dissolved ions. PA1 b) A basic component which by reaction with the emitted H.sup.+ ions may be able to emit the dissolved cations and, by this reaction, will become a more or less stable and neutral gel or solid acid. It is also possible that the acidic component and the basic component react together forming one solid component. PA1 c) Water or a water solution in which both the acidic and the basic components may dissolve working as a reaction medium. PA1 d) Eventually, accelerators, inhibitors or modifiers. PA1 a) Acidic components: MCPM&gt;DCPD=DCP&gt;OCP&gt;ACP=.beta.-TCP=.alpha.-TCP=CDA. PA1 b) Basic components: CaO=Ca(OH).sub.2 &gt;TTCP&gt;PHA=SHA&gt;.alpha.-TCP=CDA=.beta.-TCP=ACP.
For the formulation of calcium orthophosphate cements the choice is not limited to the solids appearing in the foregoing table.
Other solids may be incorporated into similar calcium containing components, specially those formed at high temperatures.
In the following Table 2 some relevant solids which may be prepared at a high temperature are shown.
TABLE 2 __________________________________________________________________________ Formation conditions and relative stability in Abbreviation Ca/P Formula water at ambient or physiological __________________________________________________________________________ temperature DCP or 1.0 CaHPO.sub.4 Formed by precipitation at high temperature, it monetite is somewhat more stable than DCPD. .beta.-TCP 1.5 Ca.sub.3 (PO.sub.4).sub.2 Formed by heating to temperature up to 1,189.degree. C. More stable than DCPD and OCP but less stable than CDA in the 6 to 8 pH range. .alpha.-TCP 1.5 Ca.sub.3 (PO.sub.4).sub.2 Formed by heating to over 1,180.degree. C. and rapid cooling. It is less stable than DCPD or OCP. SHA 1.67 Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2-2X O.sub.X Sintered hydroxyapatite. It is formed by heating in the 700 to 1,440.degree. C. range. It is as stable as CDA. TTCP 2.0 Ca.sub.4 (PO.sub.4).sub.2 O Formed by heating starting from 1,500.degree. C. It is less stable than SHA, CDA, DCPD, and OCP in slightly acidic medium. After 450.degree. C. it is less stable than Ca(OH).sub.2 and therefore it is to be expected to be more reactive. -- .infin. CaO Formed by heating CaCo.sub.3 beginning at 450.degree. C. __________________________________________________________________________
Additionally, to accelerate or to control the time necessary for setting or to improve the mechanical properties of calcium orthophosphate cements, it will be possible to use water solutions containing phosphoric, malonic, lactic, citric or other organic acids which are present in body fluids.
Given the fact that both the body fluids and the minerals are contained in bones which also comprise sodium carbonates, magnesium, sulphates, hydrochloric and hydroflouric acid, other components, particularly those mentioned in the following Table 3 may be also considered to fall within the calcium orthophosphate cement formulations.
In Table 3 a relation of solids will be shown which is relevant for the formulation of calcium orthophosphate cements, possibly appropriate as accelerators, inhibitors or even as substitute reagents for the acidic or basic components or as reaction products for the reagents which constitute a cement.
TABLE 3 __________________________________________________________________________ Compounds which contain Formulae __________________________________________________________________________ Sodium * CaNaPO.sub.4 (.alpha. or .beta. form), Ca.sub.10 Na(PO.sub.4 ).sub.7 (.alpha. or .beta. form) Ca.sub.8.5 Na.sub.1.5 (PO.sub.4).sub.4.5 (CO.sub.3).sub.2.5 * NaF * Na.sub.2 CO.sub.3, Na.sub.2 SO.sub.4, NaCl, Na orthophosphates Potassium * CAKPO.sub.4, Ca.sub.9 K(PO.sub.4).sub.5 (CO.sub.3).sub.2 * KF * K.sub.2 CO.sub.3, K.sub.2 SO.sub.4, KCl, K orthophosphates Magnesium * Ca.sub.4 Mg.sub.5 (PO.sub.4).sub.3, MgHPO.sub.4, Mg.sub.3 (PO.sub.4).sub.2.4H.sub.2 O * MgF.sub.2 * MgCo.sub.3, CaMg(CO.sub.3).sub.2, MgSO.sub.4, MgCl.sub.2, MgO, Mg(OH).sub.2 Zinc * CaZn.sub.2 (PO.sub.4).sub.2, Zn.sub.3 (PO.sub.4).sub.2.4H.su b.2 O * ZnF.sub.2 * ZnCO.sub.3, ZnSO.sub.4, ZnCl.sub.2, ZnO, Zn(OH).sub.2 Calcium * CaSO.sub.4, CaSO.sub.4.2H.sub.2 O, CaSO.sub.4. 1/2H.sub.2 O * CaF.sub.2, Ca.sub.10 (PO.sub.4).sub.6 F.sub.2 * CaCo.sub.3, CaCl.sub.2, Ca.sub.2 PO.sub.4 Cl, Ca.sub.10 (PO.sub.4).sub.6 Cl.sub.2 Biopolymers Proteins, peptides, proteoglycans, glucoseamoglycans, carbohydrates, etc. Organic acids Citric acid, malonic acid, pirmic acid, tartaric acid, etc. Inorganic acids Phosphoric acid, etc. Synthetic polymers Polylactic acid, polyglycolic acid, etc. Growth factor Transforming Growth Factor, T.G.F.-.beta., etc. __________________________________________________________________________
Solid carbonates are less desirable because carbon dioxide which may form during the reaction may cause the structure to explode, that is, it may affect structure.
The only advantage that the carbonate may bring about is that as a consequence, a solid structure may be formed at the same time which is porous and, in which structure the bone marrow may show some degree of growth.
Hydrates are less desirable as reactive components when the setting reaction water may be formed, weakening the structure.
However, DFP or OCP as reaction products may be favorable because they bind with water so they may reduce the volume of the reaction products.
With the list of possibilities shown in Tables 1 and 2, we arrive at the following components which are deemed to be appropriate, shown in decreasing acidity or basicity:
The setting reaction may be accelerated and even induced by the addition of crystal seeds of CDPD, OCP, .beta.-TCP, CDA, PHA or SHA.
Table 3 contains as well a list of other possibilities which are physiologically acceptable to initiate, accelerate or to delay the setting reaction.
Peptides and proteins as well as protoglycans may be used additionally as modifiers with the aim of obtaining a greater approximation to the composition of the bones.
Also composites with synthetic reabsorbable or non-reabsorbable synthetic polymers may be formed, being of importance the fact that growth factors like TGF-.beta. may be easily incorporated into these calcium phosphate based cements with the aim of stimulating the growth of the bone.
Among the formulations which have been previously disclosed and that are excluded from this invention, formulations based on TTCP as basic component in combination with other calcium phosphates may be cited.
U.S. Pat. No. 4,518,430 to Brown and Chow mentions as acidic components DCDP, DCP, OCP, .alpha.-TCP and .beta.-TCP.
The reaction with DCPC which takes approximately one week, may be accelerated by the addition of HA, a 48% addition causing the settling time to diminish from 22 to 8 minutes.
The combination of TTCP with, as shown in Fukase, was more successful.
By the addition of some fluoride to the blend to prevent its nucleation it was observed that the reaction product consisted in PHA.
In this last combination the inventors found that the reaction was completed in 24 hours.
Brown and Chow inventors determined a compression resistance of 37 MPa although Monma, Makishima, Mitomo and Ikegami indicate for the combination of TTCP with DCPD values comprised between and 11 MPa. The porosity is about 50% (4).
Concerning the combination of MCPM with .beta.-TCP the inventors are Mirtschi, Lemaitre and collaborators observing for 2 minutes the setting in combinations with .beta.-TCP.
The product of the reaction was DCPD and the tensile resistance varies between 0.2 and 1.1 MPa.
The tensile resistance was lowered by drying and aging in water.
The addition of calcium pyrophosphate, calcium sulphate, dihydrate or hemihydrate calcium sulphate increases the setting time up to approximately 10 minutes and the tensile resistance in dry state to about 3 MPa, by.
By any means, even in that case the resistance decreases with the aging in a saliva solution.
The combination of .alpha.-TCP with DCPD is also known by Monma and his collaborators having studied the hydration of .alpha.-tricalcic phosphate.
The reaction rate decreases with temperature and pH.
The final product was CDA and even at 60.degree. C. the setting time was of some hours and the porosity was of 60%. The compression resistance was of about 17 MPa and the tensile resistance reached 3 MPa. This combination is not adequate as a cement due to its long setting time.
Monma also studied the hydration and hardening of brushite and monetite.
The hardening was obtained by the addition of CaCo.sub.3 and water.
The final products were OCP and carbonate containing apatite.
The porosity was of approximately 75% and the tensile resistance in dry state varied within the 0.1 to 1.5 MPa range.
Due to the fact that the setting time was approximately 1 hour at a temperature between 50 and 80.degree. C., this combination was not adequate for clinical purposes.
Monma et al. are the inventors of a better performing formulation, combining .alpha.-TCP with DCPD as reagents. They found the setting time to be between 9 and 30 minutes.
The product resulting from the setting reaction was OCP which porosity was approximately 50% and the compression resistance was comprised between 14 and 15 MPa.
Concerning the formulation based on HA, this powder product with the addition of between 2 and 4% of CaO and between 2 and 6% ZnO was mixed in a chitosan solution that, as well known, is a peptide derived from chitine in a solution of malic acid.
The setting time, measured by means of an adherence test, varied from 2 1/2 to 20 minutes being the compression resistance in dry state of 2 MPa.
Concerning the formulations using collagen as modifier, .alpha.-TCP or TTCP in powder form have been combined with an antigenic collagen solution to obtain hardened products, no information having been given on setting time.
The compression resistance in the dry state was approximately 15 MPa and it has been found that when the liquid medium contained citric or malonic acid the compression resistance in dry state increased up to approximately 110 MPa.
Given the fact that the products obtained in these formulations were not calcium phosphates, these materials must not be called calcium phosphate cements and no data have been given concerning its resistance on aging in presence of humidity.
In an experiment by Oonishi and Collaboratorators carried out with test animals, a .alpha.-TCP with citric acid was used.
A histological investigation after three years demonstrated that Ca-citrate accumulated in the osteocites and that the .alpha.-TCP was transformed into apatite.
Recently a new calcium phosphate bioactive cement has been developed by Nishimura et al. 1991 .
This powder compound is a CaO--SiO.sub.2 --P.sub.2 O.sub.3 --CaF.sub.2 system glass.
The powder is blended with an amonic phosphate water solution for 1 minute, with pH 7.4, and a rate liquid/powder of 0.5.
The mix sets in 7 1/2 minutes at 20.degree. C. and its compression resistance is of approximately 16 MPa. However, after its implantation in the hindolimbar muscles of rats said resistance increased up to 70 MPa one week after its implantation.